1. Field of the Invention
The present invention relates to nanoparticles including a cucurbituril derivative. More particularly, the present invention relates to nanoparticles prepared by the aggregation of cucurbituril derivatives, a pharmaceutical composition including the nanoparticles, and preparation methods thereof.
2. Description of the Related Art
As a considerable amount of genetic information is obtained by the completion of the human genome project in the 21th century, studies about diagnosis and prognosis of various diseases have been actively conducted. Under these circumstances, the development of new drugs and new drug delivery systems therefor has been a main target of numerous studies in the biotechnology industry. Even though the development of new drugs is a high value-added industry, high risk is imposed and enormous economical support is required. Furthermore, the development of new drugs is time-consuming because a complicated clinical test is necessary to achieve commercialization after development of new drugs. On the other hand, the development of new drug delivery systems requires reduced time and cost by about ⅓ of those required for the development of new drugs and has a very high success probability. The development of new drug delivery systems has been actively made by numerous domestic or foreign academic, industrial, and governmental research institutes. An example of newly developed and currently commercially available drug delivery systems in this country is a formulation of cyclosporin (trade name: Implanta) used as an immunosuppressant, exported from: Hanmi Pharmaceutical Co. (Korea) to Novartis. Another example is the development of Ketotop (Pacific Pharmaceutical Co., Korea). Based on the successful commercialization of developed drug delivery systems, extensive studies about drug delivery systems have been conducted by the departments of chemistry, chemical engineering, pharmacy, medicine, and the like of numerous domestic universities, the research institutes of pharmaceutical companies, governmental research institutes, and industrial chemistry-related research institutes. Furthermore, there have been done studies about various drug delivery systems for genes, proteins, and organic compounds, various administration methods such as oral, transdermal, and transnasal administration, and drug delivery systems targeted to specific organs such as the brain, the kidneys, and the liver. In foreign countries, research departments for drug delivery systems are organized at almost all major universities. Major foreign companies conducting studies about drug delivery systems include Alza Corp., Elan Corporation, plc., Dura Pharmaceuticals Inc., Andrx Corp., Vivus Inc., and the like.
Development of a drug delivery system requires a drug carrier and formulation. Synthesis of various polymers used as such a drug carrier has been predominantly studied. A representative of these synthetic polymers is a biodegradable polymer. In particular, a biodegradable polymer which is non-toxic in vivo, such as polylactide (PLA), poly(lactide-co-glycolide) (PLGA), polyethyleneglycol (PEG), and poly(alkylcyanoacrylate), has been actively studied for a drug delivery system.
The following important requirements in development of a drug delivery system must be satisfied: fewer side effects; formation of a stable formulation between a drug and a drug delivery system to prevent drug loss and degeneration and to ensure a stable drug delivery; and stable drug delivery to a targeted organ or cell.
Continuous development of various drug delivery systems satisfying the above requirements is required. Hitherto, however, there are not many drug delivery systems which are excellent in all of thermoplasticity, biocompatibility, biodegradability, productivity, processability, and the like. Therefore, development of promising new drug delivery systems is required. Furthermore, active participation in development of drug delivery systems which is an important technique for new drug development is required to keep pace with worldwide studies about development of various drug delivery systems.
Cucurbituril was first reported by R. Behrend, E. Meyer, F. Rusche in 1905 (Liebigs Ann. Chem. 1905, 339, 1). According to their report, the condensation of glycoluril and excess formaldehyde in the presence of hydrochloric acid (HCl) produces an amorphous solid. Dissolution of the amorphous solid in hot concentrated sulfuric acid and then dilution of the resultant solution with water produce a crystalline substance. However, they wrongly characterized this substance as C10H11N7O4.2H2O without revealing the structure of this substance.
In 1981, this substance was rediscovered by W. Mock and coworkers. They correctly characterized it as a hexameric macrocyclic compound with the chemical formula of C36H36N24O12 which was confirmed by X-ray crystal structure determination (J. Am. Chem. Soc. 1981, 103, 7367). They named it cucurbit[6]uril. Since then, an improved synthetic method of cucurbit[6]uril has been disclosed (DE 196 03 377 A1).
In 2000, Kimoon Kim and coworkers reported the improved preparation and separation of the well-known cucurbit[6]uril and its homologues, cucurbit[n]urils (n=5, 7, 8), and identified their X-ray crystal structures (J. Am. Chem. Soc. 2000, 122, 540).
Meanwhile, WO 00/68232 discloses cucurbit[n]uril represented by Reference Diagram 1 below:

wherein n is an integer of 4 to 12.
The above-described cucurbituril derivatives are compounds including unsubstituted glycoluril monomer units.
Meanwhile, a cucurbituril derivative including substituted glycoluril monomer units was known (Angew, Chem. Int. Ed. Engl. 1992, 31, 1475). According to this document, decamethylcucurbit[5]uril including five dimethanodimethylglycoluril monomer units is synthesized by condensation between dimethylglycoluril and formaldehyde.
Cucurbituril is a macrocyclic compound and has a lipophilic cavity and two hydrophilic entrances at upper and lower portions. In this respect, lipophilic interactions occur in the cavity of cucurbituril, and hydrogen bonds, polar-polar interactions, and positive charge-polar interactions occur in the two entrances having six carbonyl groups. Therefore, cucurbituril has retention capacity for various compounds by very stable non-covalent bond with these compounds (see Table 1).
TABLE 1Non-covalent coupling constant between cucurbituril and compoundsGuest moleculeKfGuest moleculeKfCH3CH2COOH5.9 × 102 M−1Phe1.4 × 103 M−1NH2(CH2)6NH22.7 × 106 M−1L-Ala1.0 × 103 M−1Me(CH2)4NH22.4 × 104 M−1L-Val1.4 × 103 M−1H2N(CH2)5OH6.9 × 102 M−1Phe-gly1.1 × 103 M−1H2N(CH2)2COOH2.3 × 103 M−1Leu-gly3.7 × 102 M−1H2N(CH2)2CN4.4 × 102 M−1Gly-val1.5 × 103 M−1
As shown in Table 1, cucurbituril forms a complex, particularly, with a compound having an amino group or a carboxyl group by very stable non-covalent linkage. Based on such characteristics, studies about application of cucurbituril in various areas have been continuously conducted.
Recently, the present inventors reported a complex formation between oxaliplatin approved as an anticancer agent by the Food Drug Administration (FDA) and cucurbituril used as a drug delivery system by a stable non-covalent bond (PCT/KR02/01755). Furthermore, the present inventors reported an enhancement of DNA binding capacity by cucurbituril-containing pseudo-rotaxane and a use of a cucurbituril-based dendrimer as a gene delivery system [KR01-7169, Angew. Chem. Int. Ed., 2000 and 2001].
In addition, the present inventors found that a self-assembled monolayer made of cucurbituril, which is formed on a gold surface, has a reproducible and stable non-covalent binding capacity with proteins such as lysozyme and glucose oxidase (GOD).
In this regard, it is anticipated that cucurbituril cannot be used as a drug delivery system only for a single molecule drug having an amine group, an ammonium group, or a carboxyl group, but also for a protein or polypeptide drug. However, cucurbituril has a low solubility and no active functional groups that can be easily substituted by various substituents, and thus, its utility is extremely limited. For this reason, cucurbituril is subsidiary to cyclodextrin which is an existing promising drug delivery system. In spite of very excellent retention capacity of cucurbituril, extensive studies about a use of cucurbituril as a drug delivery system have not been conducted.
Recently, while searching for solutions to overcome the limitations in use of cucurbituril as a drug delivery system, the present inventors developed hydroxycucurbituril having twelve hydroxyl groups and diaminophenylcucurbituril having two aminophenyl groups as a result of introducing active substituted groups to cucurbiturils limitedly used [see Reference Diagram 2: Korean Patent Application No. 2003-0008453, PCT/KR02/02213].

Various substituents can be easily introduced into the above-described hydroxycucurbituril, which enables synthesis of various cucurbituril derivatives.
Therefore, under the necessity of development of new drug delivery systems, the present invention was completed based on the above-described non-covalent binding properties of cucurbiturils and easy introduction of various substituents into cucurbituril derivatives.